Study summary · research use only
AMPK-independent inhibition of human macrophage ER stress response by AICAR
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This in vitro study using human macrophages examined AMPK-independent effects of the AMP-mimetic AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) on endoplasmic reticulum (ER) stress responses triggered by the saturated fatty acid palmitate under hypoxia-potentiated inflammation, and by the ER stressors thapsigargin and tunicamycin. The abstract reports that AICAR suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines, acting independently of AMPK or of AICAR's conversion to ZMP (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate), instead requiring uptake via the nucleoside transporters ENT1 or CNT3. AICAR did not affect initiation of the ER stress response but was reported to inhibit expression of major ER stress transcriptional effectors, and to inhibit autophosphorylation of the sensor IRE1α while activating its endoribonuclease activity in vitro.
Abstract
Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty acids (SFA), and endoplasmic reticulum (ER) stress responses essentially contribute to pro-inflammatory signalling. AMP-activated protein kinase (AMPK) is a central metabolic regulator with established anti-inflammatory actions. Whether pharmacological AMPK activation suppresses SFA-induced inflammation in a human system is unclear. In a setting of hypoxia-potentiated inflammation induced by SFA palmitate, we found that the AMP-mimetic AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) potently suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines. Furthermore, AICAR inhibited macrophage ER stress responses triggered by ER-stressors thapsigargin or tunicamycin. Surprisingly, AICAR acted independent of AMPK or AICAR conversion to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP) while requiring intracellular uptake via the equilibrative nucleoside transporter (ENT) ENT1 or the concentrative nucleoside transporter (CNT) CNT3. AICAR did not affect the initiation of the ER stress response, but inhibited the expression of major ER stress transcriptional effectors. Furthermore, AICAR inhibited autophosphorylation of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), while activating its endoribonuclease activity in vitro. Our results suggest that AMPK-independent inhibition of ER stress responses contributes to anti-inflammatory and anti-diabetic effects of AICAR.
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